αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Abstract

The transforming growth factor (TGF)-␤-inducible integrin ␣v␤6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-␤. Herein , we show that ␣v␤6 is overexpressed in human kidney epithelium in membranous glomerulonephritis , diabetes mellitus , IgA nephropathy , Goodpasture's syndrome , and Alport syndrome renal epithelium. To assess the potential regulatory role of ␣v␤6 in renal disease , we studied the effects of functionblocking ␣v␤6 monoclonal antibodies (mAbs) and genetic ablation of the ␤6 subunit on kidney fibrosis in Col4A3 ؊/؊ mice , a mouse model of Alport syndrome. Expression of ␣v␤6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with ␣v␤6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in ␤6-deficient Alport mice. Transcript profiling of kidney tissues showed that ␣v␤6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-␤ RII treatment , suggesting shared regulatory functions of ␣v␤6 and TGF-␤. These findings demonstrate that ␣v␤6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

Induction of an Epithelial Integrin αvβ6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-β1 and Increased Collagen Production

“…23 Likewise, lack of the ␤6 integrin gene protects against tubulointerstitial renal fibrosis in mice with unilateral urethral obstruction 63 and blockade of integrin ␣v␤6 protects against renal fibrosis in a murine model of Alport's syndrome. 24 In transgenic mice overexpressing human integrin ␤6 in the epithelium, chronic ulcers with areas of severe fibrosis develop, and TGF-␤1 expression significantly increases in lesions as compared with normal skin. 64 These various lines of evidence suggest that integrin-␣v␤6-mediated TGF-␤ activation is of general importance in the development of fibrosis in multiple epithelial organs, and the same mechanism may well contribute to fibrosis and other pathological outcomes in CMV disease.…”

“…Mice lacking the ␤6 subunit show increased inflammation and decreased fibrosis, both of which processes are strongly regulated by TGF-␤1. 18,23,24 Recent work has provided evidence for the induction of TGF-␤1 in a variety of cells and tissues on CMV infection. TGF-␤1 was released in increasing amounts from splenocytes infected with rat CMV in vitro.…”

Preclinical SPECT/CT Imaging of αvβ6 Integrins for Molecular Stratification of Idiopathic Pulmonary Fibrosis

“…Novel strategies to improve the outcome for these patients are urgently required, and to facilitate a stratified approach to the treatment of IPF it is important to identify a biomarker that reflects relevant biology. The epithelial-restricted integrin avb6 is an attractive target for the treatment of IPF because of its important role in regulating integrin-dependent transforming growth factor b activation (25), its pathogenic role in several different experimental models of fibrosis (25,26,28,(35)(36)(37), and its increased expression on alveolar epithelial cells in fibrotic areas of lung in patients with IPF (27,28). The expression of avb6 integrin is temporally and spatially linked to the development of fibrosis, with upregulation of integrin in the alveolar epithelium being detected before the development of fibrosis and persisting within the fibrotic lesions (26).…”

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

“…28 Mice deficient in the collagen 4A3 isoform (COL4A3) develop a progressive fibrosing glomerulonephritis similar to Alport syndrome in humans.…”